TASK DEPENDENCY OF SLEEP LOSS-INDUCED NEUROBEHAVIORAL FUNCTIONING IMPAIRMENTS

Rachael Muck

doi:10.7273/000007918

Current neurobiological theories of sleep/wake regulation and neurobehavioral functioning during sleep loss do not account for trait-like, inter-individual and task-dependent differences. Neuroimaging evidence suggests that aspects of cognition may have dissociable neurological mechanisms which may underlie these task-dependent inter-individual differences, however, the neurological mechanisms have yet to be fully elucidated. The purpose of this dissertation is to investigate the modulators of task-dependent sleep loss-induced neurobehavioral functioning and its inter-individual differences which may provide insight into the mechanisms underlying these differences. In Chapter 2, we investigate whether the temporal profiles of neurobehavioral functioning are task-dependent. Following three days of simulated shiftwork schedules and accounting for individual differences in the circadian and homeostatic processes, a 24-hour constant routine protocol was used to unmask the endogenous circadian rhythm. The homeostatic and circadian processes were statistically separated, thus exposing the endogenous circadian rhythmicity for each neurobehavioral measure: vigilant attention (PVT), subjective sleepiness (KSS), and cognitive throughput (DSST). We found there were no differences in the timing of the endogenous circadian rhythm between these neurobehavioral measures. These results suggest there is one circadian modulator of neurobehavioral functioning and that aspects of cognition are subjected to the same biologically driven time-of-day effects, which supports the current view of circadian rhythmicity exerting a top-down control of neurobehavioral functioning. In Chapter 3, we utilize a pharmacological approach to assess how phenotypic vulnerability and resiliency to total sleep deprivation (TSD) are modulated by caffeine and modafinil, wake-promoting agents with distinct mechanisms, across various neurobehavioral outcomes. Caffeine, modafinil, and placebo were repeatedly administered during 38 h TSD from 17–29 h of wakefulness to assess the effects on vigilant attention (PVT), cognitive throughput (DSST), subjective sleepiness (KSS), positive and negative affect (PANAS), behavioral drowsiness (lane position variability), and cognitive stability and cognitive flexibility (reversal learning paradigm). The drug effects on systematic inter-individual differences, distribution of between-subjects variability, and clustering of neurobehavioral components were investigated. Compared to placebo, caffeine and modafinil generally reduced systematic inter-individual differences, group-average impairment, and the distribution of inter-individual differences. Caffeine and modafinil were equally effective in improving subjective sleepiness, vigilant attention, cognitive throughput, cognitive flexibility, and behavioral drowsiness (on the latter portion of the task) impairments for vulnerable individuals. Resilient individuals did not benefit from either stimulant for subjective sleepiness and vigilant attention, but did benefit from modafinil on cognitive throughput and caffeine on cognitive flexibility. Vulnerability and resiliency to behavioral drowsiness (first portion of the task) and cognitive stability were differentially modulated by caffeine and modafinil, with vulnerable individuals benefiting more from caffeine on behavioral drowsiness and more from modafinil on cognitive stability; the opposite was found for resilient individuals. Components of inter-individual differences across neurobehavioral outcomes changed more with caffeine than placebo or modafinil. These results provide evidence of caffeine and modafinil contributing to sleep loss-induced phenotypic vulnerability and resiliency across neurobehavioral outcomes. The distinct underlying mechanisms of caffeine and modafinil, adenosinergic-acting and dopaminergic-acting, respectively, suggest these pathways may be involved in modulating TSD-induced inter-individual and task-dependent differences. Chapter 4 extends upon the findings of Chapter 3 and utilizes a pharmacogenetic approach to determine whether the underlying neurological mechanisms for TSD-induced impairments in cognitive flexibility are distinct from those of vigilant attention and to further investigate how the adenosinergic and dopaminergic systems differentially contribute to these impairments. Caffeine and modafinil effects on vigilant attention and cognitive flexibility (measured with a reversal learning task) were further analyzed by a priori selected genetic polymorphisms related to dopamine and adenosine: adenosine A2A receptor (ADORA2A), dopamine D2 receptor (DRD2), and catechol-O-methyltransferase (COMT). We found dissociable pharmacogenetic effects on vigilant attention and cognitive flexibility, with ADORA2A modulating modafinil’s wake-promoting effects on cognitive flexibility but not vigilant attention and COMT modulating caffeine and modafinil’s effects on vigilant attention but not cognitive flexibility. Our findings provide evidence that cognitive flexibility impairment is not just a downstream effect of vigilant attention deficits and that there are dissociable adenosinergic and dopaminergic mechanisms underlying TSD-induced deficits in these aspects of neurobehavioral functioning. These results support growing evidence contradicting the long-standing theory that sleep loss-induced neurobehavioral impairment is a unitary phenomenon driven by vigilant attention. The findings in this dissertation provide insights into the modulators of task-dependent sleep loss-induced neurobehavioral functioning and its inter-individual differences. We did not find evidence of more than one circadian modulator of neurobehavioral functioning; therefore, neurobehavioral functioning is predictable as a function of circadian time (Chapter 2). In contrast, the task-dependent inter-individual differences during sleep loss were modulated in part by two distinct systems: sleep-promoting adenosine and wake-promoting dopamine (Chapters 3 and 4).

TASK DEPENDENCY OF SLEEP LOSS-INDUCED NEUROBEHAVIORAL FUNCTIONING IMPAIRMENTS

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